Tumor development is a complex process that relies on interaction and communication between a number of cellular compartments. Much of the mass of a solid tumor is comprised of the stroma which is richly invested with extracellular matrix. Within this matrix are a host of matricellular proteins that regulate the expression and function of a myriad of proteins that regulate tumorigenic processes. One of the processes that is vital to tumor growth and progression is angiogenesis, or the formation of new blood vessels from preexisting vasculature. Within the extracellular matrix are structural proteins, a host of proteases, and resident pro- and antiangiogenic factors that control tumor angiogenesis in a tightly regulated fashion. This paper discusses the role that the extracellular matrix and ECM proteins play in the regulation of tumor angiogenesis.

Epithelial ovarian cancer (EOC) is the most lethal gynecologic cancer and also one of the most poorly understood. Other health issues that are affecting women with increasing frequency are obesity and diabetes, which are associated with dysglycemia and increased blood glucose. The Warburg Effect describes the ability of fast-growing cancer cells to preferentially metabolize glucose via anaerobic glycolysis rather than oxidative phosphorylation. Recent epidemiological studies have suggested a role for hyperglycemia in the pathogenesis of a number of cancers. If hyperglycemia contributes to tumour growth and progression, then it is intuitive that antihyperglycemic drugs may also have an important antitumour role. Preliminary reports suggest that these drugs not only reduce available plasma glucose, but also have direct effects on cancer cell viability through modification of molecular energy-sensing pathways. This review investigates the effect that hyperglycemia may have on EOC and the potential of antihyperglycemic drugs as therapeutic adjuncts.

Epithelial ovarian cancer (EOC) comprises approximately 90% of ovarian cancers and arises from the surface epithelium. Typical treatment of EOC involves cytoreductive surgery combined with chemotherapy. More recent therapies have targeted the tumor vasculature using antiangiogenic compounds such as thrombospondin-1 (TSP-1). TSP-1 mimetic peptides such as ABT-510 have been created and have been in various clinical trials. We have previously shown that ABT-510 reduces abnormal vasculature associated with tumor tissue and increases the presence of mature blood vessels. It has been hypothesized that treatment with antiangiogenic compounds would allow increased delivery of cytotoxic agents and enhance treatment. In this study, we evaluated the potential role of ABT-510 and various chemotherapeutics (cisplatin and paclitaxel) on tumor progression, angiogenesis, and the benefits of combinational treatments on tissue uptake and perfusion using an orthotopic syngeneic mouse model of EOC. Animals were treated with ABT-510 (100 mg/kg per day) alone or in combination with cisplatin (2 mg/kg per 3 days) or paclitaxel (10 mg/kg per 2 days) at 60 days after tumor induction. Radiolabeled and fluorescently labeled paclitaxel demonstrated a significant increase in tumor uptake after ABT-510 treatment. Combined treatment with ABT-510 and cisplatin or paclitaxel resulted in a significant increase in tumor cell and tumor endothelial cell apoptosis and a resultant decrease in ovarian tumor size. Combined treatment also regressed secondary lesions and eliminated the presence of abdominal ascites. The results from this study show that through vessel normalization, ABT-510 increases uptake of chemotherapy drugs and can induce regression of advanced ovarian cancer.

Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy and is often not diagnosed until late stages due to its asymptomatic nature. Women diagnosed with EOC typically undergo surgical debulking followed by chemotherapy; however, disease recurrence often occurs. In this study, we evaluated the ability of the thrombospondin-1 mimetic peptide, ABT-898, to regress established, late-stage tumors in a mouse model of human EOC. Ovarian tumors were induced and ABT-898 treatment was initiated at time points that were representative of late stages of the disease to study tumor regression. ABT-898 induced tumor regression and reduced the morbidity of treated animals compared with controls. Analysis of tumors from ABT-898-treated animals showed reduced abnormal tumor vasculature, decreased expression of the proangiogenic compound VEGF, and reduced tumor tissue hypoxia. ABT-898 treatment initiated at late-stage disease also significantly prolonged disease-free survival compared with control animals. Results from this study show that ABT-898 is capable of regressing established ovarian tumors in an animal model of the disease. As most women are detected at advanced stage EOC, ABT-898 may improve our treatment of ovarian cancer. Mol Cancer Ther; 10(10); 1876-85. Ó2011 AACR.